Quinapril is a generic term used to identify a chemical compound, 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetra hydro-3-isoquinoline carboxylic acid hydrochloride (S,S,S): ##STR1##
This compound and its pharmaceutically acceptable salts are active as angiotensin converting enzyme inhibitors and thus are antihypertensive agents. The compound and its use are covered in U.S. Pat. No. 4,344,949.
The compound may be prepared from 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid by first protecting the carboxylic acid group, preferably as an ester, e.g., with a lower alkyl, of from one to four carbon atoms, benzyl or trimethylsilyl group. The protected carboxylic acid compound is coupled to an N-protected amino acid, e.g., glycine or L-alanine, protected on nitrogen with t-butyloxycarbonyl or benzyloxycarbonyl. The coupling is carried out by any of a variety of standard peptide coupling techniques as disclosed, for example, in "The Peptides. Analysis, Synthesis, Biology, Vol. 1 Major Methods of Peptide Bond Formation, Part A", ed. E. Gross, J. Meierhofer, Academic Press N.Y. (1979). An especially useful method involves the use of a dehydrating agent, such as dicyclohexylcarbodiimide alone or in the presence of reagents forming reactive esters, e.g., 1-hydroxybenzotriazole, in suitable aprotic solvents such as dimethylformamide, acetonitrile, tetrahydrofuran or chlorinated hydrocarbons. This gives the intermediate (N-protected-2-aminoacyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid esters. These may then be either partially or totally deblocked depending on the protecting groups chosen, using anhydrous acids, e.g., hydrochloric acid in acetic acid or trifluoroacetic acid in methylene chloride, or hydrogen gas and a catalyst to give the intermediate dipeptide either in free form or protected as an ester.
The compound may then be prepared by reacting the intermediate dipeptide or its ester derivative with .alpha.-keto-4-substituted phenylbutyric acid or its lower alkyl ester derivatives under dehydrating and reducing conditions. Preferred dehydrating agents include molecular seives in aprotic solvents and preferred reducing agents include sodium cyanoborohydride or hydrogen gas with a catalyst.
Alternatively, the dipeptide or its ester derivative may be reacted with an .alpha.-halo-4-substituted phenylbutyric acid or its ester in the presence of a suitable basic reagent, such as triethylamine or alkali carbonates or bicarbonates, in a solvent, to give the compound. Ester protected products may be hydrolyzed under basic or acidic reaction conditions to free acid derivatives, or, in the case of benzyl esters, catalytic hydrogenolysis may be preferred.
Alternately, the compound may be prepared in a different manner. This consists of applying either of the two methods described above for the attachment of the 2-(4-phenylbutyric acid) moiety to the protected dipeptide, first to glycine or L-alanine, which may be protected as an ester, to give N-[2-(4-phenylbutyric acid)]-substituted glycine or L-alanine derivative.
After selective deblocking of the acid moiety on the glycine or alanine portion of the product, the resulting monoacid may be coupled, either directly or subsequent to suitable blocking of the amino group, via standard peptide coupling procedures to the 1,2,3,4-tetrahydro-3-isoquinoline carboxylate, protected as an ester. Selective or complete removal of the ester groups and any amine protectig groups yield the compound.
The products are obtained typically as a mixture of diastereoisomers which can be separated by standard methods of fractional crystallization or chromatography.
The compounds of this invention form acid salts with various inorganic and organic acids which are also within the scope of the invention. The pharmaceutically acceptable acid addition salts of the compounds of the present invention may be prepared by conventional reactions by reacting the free amino acid or amino ester form of the product with one or more equivalents of the appropriate acid providing the desired anion in a solvent or medium in which the salt is insoluble, or in water and removing the water by freeze drying. The salts of strong acids are preferred such as the salts of hydrochloric, hydrobromic, sulfuric, nitric, acetic, fumeric, malic, maleic and citric acids.
Large scale recrystallization of quinapril regardless of the method whereby it is produced involved the problem that the crude final products were not purifiable by conventional organic chemistry techniques. In order to obtain material of reasonable purity the crude products were dissolved in water, the insoluble gummy impurities filtered off and the products isolated by freeze drying. This proved to be expensive and time consuming.
The impurities formed during the last synthetic step are in the amounts of from 10 to 30% when either trifluoroacetic acid or HCl gas/CH.sub.2 Cl.sub.2 are used to remove the t-butyl group from the pure t-butylester recursor. Examination of the byproducts by thin layer chromatography and NMR revealed that they are a complex of the drug, the corresponding diketopiperazine (shown below) and two other unidentified impurities. There is no starting material present. ##STR2##
The presence of the above complex has foiled all previous attempts to purify the drug substance by recrystallization.